Disruption of atherosclerotic plaques and formation of occlusive platelet thrombi remains a leading cause of morbidity and mortality in the United States. Antiplatelet therapies are used in preventing arterial thrombosis and myocardial infarction in high risk patients with acute coronary syndromes (ACS), atherothrombotic disease, and in patients who have undergone percutaneous coronary intervention (PCI). Current antiplatelet therapy for secondary prevention of vascular events mainly consists of oral administration of aspirin and thienopyridines. Patients with a higher risk of thrombosis while undergoing coronary interventions are also often treated with intravenous GP IIb/IIIa antagonists in addition to aspirin, thienopyridine, and heparin. Although dual antiplatelet therapy has been shown to attenuate ischemic event occurrence during ACS and PCI, drug response variability, the persistent occurrence of ischemic events, and the increased risk of bleeding events remain major concerns. Notably, approximately 10% of patients still suffer from recurrent ischemic events within one year of treatment. Thus, there is a need to identify improved therapeutic strategies.
Pepducin compounds are lipidated peptides that target specific intracellular loops of G-protein-coupled receptors (GPCRs) and are allosteric modulators of GPCR activity. The lipid moiety facilitates translocation across the plasma membrane where pepducin compounds modulate signaling of their cognate receptors. See Covic et al., PNAS, 2002, 99(2):643-64. The thrombin receptor, PAR1, is a GPCR that is a target for therapeutic intervention in conditions or diseases associated with undesirable platelet aggregation. See Chintala et al., J Pharmacol Sci. 2008, 108(4):433-438 and Leger et al., Circulation, 2006, 113(9):1244-1245. A pepducin compound, PZ-128 (also known as P1pal-7) has been reported. See WO/2010/118435. See also US Published Application 2007/0179090 and Wielders et al., J Thromb Haemost, 2007, 5(3):571-576.